Process for the manufacture of 10-acyloxy-19-nor-steroids



Ueit dmsato Patent 3 11s 461 Paocnss non rrin rirnomracrnnn orm-AcitroxY-ra-Non-srnnoms fisher Ieger and Kurt Sehafiner, Zurich,tlwitzerlanal,

The present invention provides a new process for the manufacture oflfi-acyloxy-l9-norsteroids starting from A -3-oxo-l9-hydr0xysteroids.The products of the present process are valuable intermediates for themanufacture of compounds which have a very high pharmacological actionand have been used on an especially large scale in therapy in the recentpast. This is. particularly true of the compounds which belong to theseries of the 19-norsteroids, for example l9-nortestosterone,l9-norprogesterone and ot the oestratrienes having an aromatic ring Awhich occur in nature, among which, for example, 19-n0rtestosterone,l9-nor-l7-metl1yltestosterone, A-3-oxol7B-l1ydroxy-l7a-ethinyl-l9-norandrostene, -19 nor17ccacetoxyprogesterone, 6 dehydro-l9-nor-l7a-acetoxyprogesterone,oestrone and oestradiol are of special value because of their anabolic,progestative, ovulation-inhibiting and oestrogenic action.

Hitherto, the 1Q-hydroxy-l9-norsteroids and lO-acyloxy-lQ-norsteroidshave been accessible only by the detour via the 5:10-unsaturatedl9-norsteroids, for example by epoxidation of A -3-oxo-19-nor compoundsand subsequent scission of the epoxide (US. Patent 2,729,654) or bymicrobiological oxidation (US. Patent 2,888,384).

It has now been observed that when a l9-O-radical is formed in a A-3-oxo-l9-hydroxysteroid the angular substituent in position 10 iseliminated and a l9-nor-steroid is formed, more especially by treatmentwith a heavymetal acylate having an oxidizing action, whereupon thestarting material is converted into a 10-acyloxy-19-norsteroid. i

Thus, according to the process of the invention 21 A3-oxo-l9-hydroxysteroid is treated with a heavy-metal acylate having anoxidizing action.

Heavy-metal acylates having an oxidizing action are, above all, acylatesof tetravalent lead whose acid component is derived from a loweraliphatic, cycloaliphatic, araliphatic or aromatic acid; for example,they may be lead (IV) acetate, pr-opionate, trimethylacetate,trifiuoracetate, hexahydrobenzoate,phenylacetate, benzoate or the like.7

The treatment according to the invention is carried out as follows: Thestarting material, or, if desired, a mixture thereof with a weakinorganic or organic base, for example an alkaline earth metal carbonatesuch as calcium carbonate, barium carbonate or strontium carbonate, or atertiary organic base such as pyridine, together with an excess of oneof the aforementioned heavy-metal acylates, is heated in an apolarsolvent, for example to the boiling temperature of the latter,preferably to a temperature above 60 C., and the10-acyloxy-l9-norsteroid obtained as the process product is isolated andseparated from any starting material left nnreacted by chromatographicpuritication.

Particularly suitable solvents are aliphatic, cycloaliphatic andaromatic hydrocarbons, for example hexane, heptane, cyclohexane,methylcyclohexane, dim ethylcyclohexane, benzene and the like. i

in general, the time taken by the reaction depends on the reactiontemperature and ranges preferably from to 29 hours. i

aildfihl Patented Apr. 13, 1965 In the A -3-oxo-IOfl-acyloxy-l9-norsteroids obtained, an oxo group present can bereduced, for instance a l7-oxo group can be selectively converted into al7fl-hydroxyl group, for example with a mild reducing metal hydridecomplex of the type of the lithium trialkoxy aluminum hydrides, such aslithium trimethoxy or lithium tritertiary butoxy aluminum hydride, in asuitable solvent, such as an ether, for example in diethyl ether,tetrahydrofuran, dioxane or a mixture of the latter with an aromatichydrocarbon, for example with benzene or toluene, or by treatment with aGrignard compound or an organo-metal compound of the type of lithiumacetylide or methyl lithium, for example in the above-mentionedsolvents; if desired, this conversion may take place simultaneously withthe introduction of a saturated or unsaturated hydrocarbon radical inposition 17a. There may also be introduced in the products of theinvention an additional double bond in position 1-2. more especially bytreatment with a dehydrogenating agent, for example with a quinone suchas 2:3-dichloro-4:S-dicyanobenzoquinone or tetracyanobenzoquinone, in asuitable solvent, for example in a lower aliphatic, preferably tertiaryalcohol, such as tertiary butanol or tertiary amyl alcohol, or in acyclic ether such as d-ioxane, or with selenous acid or with aderivative of selenous acid. Particularly suitable are selenium dioxideand esters of selenous acid in a solvent that is inert towardsoxidation, for example in a lower aliphatic carboxylic acid, such asacetic or propionic acid, or in a cyclic ether such as dioxane ortetrahydrofuran. The A -3oxo-10fi acyloxy 19 norsteroids obtained inthis manner can be converted in a simple manner into compounds having anaromatic ring A, of the type of oestrone, for example by irradiation(see Helv. Chim. Acta 43, page 500 [1960]), or by reduction, for examplewith zinc in glacial acetic acid.

As starting materials for use in the present process there are suitableA -3-oxo-19-hydroxysteroids, for example of the androstane, pregnane,cholestane, spirostane, and cardanolide series. They may contain in oneor more than one of the positions 1, 2, 6, '7, 8, 9, 11, 12, 14-17 andin the side chain further substituents, for example alkyl (such asmethyl) groups or halogen atoms, also functionally converted (that is tosay esterified or etherified) hydroxyl groups and free, ketalized orenolized oxo groups. The compounds may also contain one or more than onedouble bond, more especially in 6:7-position, in ring D and in the sidechain.

Particularly useful starting materials are the A-3-oxo-l9-hydroxyandrostenes and ample A -3-oxo-l9-hydroxyandrostene,

A 8: 17-dioxo-19-l1ydroxyandrostene,

A oxo-l7B-acyloxy-19-hydroxyandrostenes,

A -3-oxo-l7fi-acyloxy-l7a-alkyland -l7a-alkenyl-l9-hydroxyandrostenes,such, for example, as A 3-oxo-l7fi acyloxy-17ot-rnethyl-, -l7a-ethyl-,l7u-vinyl-, -17OL'tI'ifiuorovinyl-, -17u-allyl'-,17a-methallyl-19-hydroxyandrostenes; furthermore A -3:ZO-dioxo-lQ-hydroxypregnene,

13 -3:ZO-dioxo-17a-acyloxy-l9-hydroxypregnenes,

A -3 :20-dioxo-l7dz2l-diacyloxy-19-hydroxypregnenes,

A -3:20-dioxo-6a-methyl-l9-hydroxypregnene, and the corresponding6-dehydro compounds, such as E -3:17- dioxo l9 hydroxyandrostadiene, 'A-3-oxo-l7fi-acyloxy-19-hydroxyandrostadiene and A-3z2il-dioxo-l7aacyloxy-19-hydroxypregnadienes.

pregnenes, for ex- The atone-mentioned starting materials are known or,if new, can be prepared according to known methods. Advantageously theyare prepared from. 19-unsubstituted steroids either by microbiologicaloxidation, or by the process, wherein for example, 3-oxygenated19-unsubstituted 6fi-hydroxy-steroids are treated with a compoundcontaining monovalent positive iodine, or with a metal acylate having anoxidizing action such, for example, as lead tetraacetate, and theresulting 3-oxygenated 65:19- oxidosteroids are converted under reducingor acylolytic conditions, before or after introduction of the A -3-oxogrouping, into 19-hydroxy or 19-acyloxy compounds respectively. Thelatter are easy to hydrolyse to 19-hydroxysteroids, if desiredselectively. Such processes are described, for example, in copending US.patent applications Serial No. 208,610, filed July 9, 1962, and SerialNo. 235,850, filed February 6, 1962, by Albert Wettstein et al.

The conversion of the A -3-oxo-10-acyloxy-19-nor-steroids obtained bythe present process into the therapeutically valuable IO-unsubstituted19-norsteroids has been described in our copending US. patentapplications Serial No. 278,775, filed May 7, 1963, and Serial No.278,776, filed May 7, 1963, according to which a A-3-oxo-10-acyloxy-19-nor-steroid is treated either with a reducingagent,

for example with zinc in acetic anhydride or with chro- I mium II salts,and, if desired, the resulting A or A -3-oxo-19-norsteroid is convertedby known methods into a A -3-oxo-19-norsteroid, or the A -3-oxo-10-acy1-oxy-19-norsteroid is heated, whereupon the compound having an aromaticring A, of the oestrone type, or its 6-dehydro derivative, is obtaineddirectly in a single stage.

In the above esters the acid radicals are preferably those of aliphatic,cycloaliphatic, araliphatic, heterocyclic or aromatic carboxylic acids,preferably such as contain 1 to carbon atoms, for example formates,acetates,

propionates, butyrates, trimethylacetates, oenanthates, caproates,decanoates, cyclopentyl-propionates, valerates, benzoates, furoates,hexahydrobenzoates, phenylpropionates, trifiuoroacetates, ethyl ormethyl carbonates, and the like.

The following examples illustrate the invention.

Example 1 2 grams of lead tetraacetate are dried for 45 minutes in ahigh vacuum and then, in admixture with 2 grams of calcium carbonate,boiled in 200 cc. of absolute benzene for a short time. The cooledmixture is then mixed with 2 grams of A -3:17-dioxo-19-hydroxyandrosteneand the batch is heated at the boil for 14 hours, then poured intowater, extracted with ether and the organic phase is dried overanhydrous sodium sulfate and evaporated under vacuum, to yield 2.03grams of an oily crude product which is chromatographed on neutralalumina (activity III).

Benzene and a 9: l-mixture of benzene and ether elute 1210 mg. ofcrystals which, after three recrystallizations from acetonezpetroleumether, have a constant melting point of 195-196" C. Optical rotation[ocl =+102 (c.=0.87). The infra-red absorption spectrum (in chloroform)displays bands at 1732, 1668, 1628 and 1245 cm.- Ultra-violet spectrum::243 m (e=12,.800). The product is A -3:17-dioxo-10,8-acetoxyoestrene.

With an ether+ethy1 acetate mixture there are obtained 572 mg. ofcrystalline starting material, melting at 164 C., after onecrystallization from acetone+petroleum ether. As revealed by the mixingmelting point, infrared spectra and thin-layer chromatogram [solventsystem: 9:1-mixture of benzene and methanol] the product is identicalwith 13 -3:17-dioxo-19-hydroxyandrostene.

Example 2 A stirred suspension of 4.0 grams of previously dried leadtetraacetate and 2.0 grams of calcium carbonate in 200 cc. ofcyclohexane is mixed with 1.0 gram of 19- hydroxyprogesterone. Themixture is stirred under reflux for 20 hours, then cooled and filteredthrough Celite; the residue is exhaustively washed with hexane, thefiltrate is extracted with a 10% potassium iodide and sodium thiosulfatesolution, dried and evaporated under vacuum at about C. The resulting,partially crystalline, crude product is freed from adhering startingmaterial by being dissolved in benzene and chromatographed on 20 timesits own weight of alumina (activity III). By means of the same solvent atotal of 635 mg. of pure A -3:20-dioxo- 10-acetoxy-19-norpregnene iseluted. Its infra-red spectrum contains absorption bands, inter alia, at1735, 1700, 1670, 1620, 1245 and 10,020 cm.- Ultra-violet spectrum: lt=242 ma (log 6 4.05).

Mixtures of benzene and ethyl acetate further yield a total of 315 mg.of 19-hydroxyprogesterone melting at 163-165 C.

Using identical reaction conditions and 500 mg. of M320-dioxo-17a-acetoxy-19-hydroxypregnene (melting at 240-242" C.) asstarting material, followed by a suitable purification of the resultingcrude product, there are obtained 285 mg. of A-3:20-dioxo-10:17a-diacetoxy-19- norpregene melting at l99201 C.

Example 3 3.5 grams of dry lead tetraacetate are suspended in 200 cc. ofmethylcyclohexane, mixed with 2.0 grams of previously dried calciumcarbonate, and the whole is stirred and heated for 15 minutes at 100 C.570 mg. of A -3-oxo- 17t3-decanoyloxy-19-hydroxyandrostene, melting at99-,

100 C., are then added, and the reaction mixture is refiuxed for 5hours. The cooled solution is filtered to remove inorganic constituents,the residue is washed with mcthylcyclohexane, and the combined filtratesare evaporated under vacuum at about 35 C. The resulting crude productis dissolved in benzene, and as described in Example 2, chromatographedon alumina, to yield 405 mg. of pure .A-3-oxo-17t3-decanoyloxy-10-acetoxy-19-norandrostene in the form of acolorless oil. The infra-red spectrum of the compound containsabsorption bands, inter alia, at 1740 (broad), 1667, 1615 and 1245 cmfWhen lead tetraacetate is replaced by lead tetrabenzoate, the finalproduct of the reaction is likewise amorphous A-3-oxo-1O-benzoyloxy-17fi-decanoyloxy-19 norandrostene whose infra-redspectrum contains absorption bands, inter alia, at 1725, 1670, 1620,1285 and 1120 CHIC-1.

In an analogous manner there is obtained, for example, fromM-S-oxo-l7ti-acetoxy-l7ot-methyl-19 hydroxy androstene, in a yield of 70to 80% of theory, crude A -3- oxo-lO:17 8-diacetoxy-17a-methyl-19norandrostene, and A -3-oxo-10-benzoyloxy-17fi-acetoxy 17a methyl 19-norandrostene respectively, which compounds can be used withoutpreliminary purification, for example for conversion into A or A-3-oxo-17t3-acetoxy-17a-methyl-19- norandrostene according to our patentapplication Serial No. 278,775, filed May 7, 1963.

Example 4 A solution of 200 mg. of A -3:17-dioxo-106-acetoxy-19-norandrostene and 400 mg. of 2:3-dichloro-4z5-dicyanopara-quinone in 60cc. of dioxane is stirred and heated for 17 hours at the boil, thenevaporated to dryness under vacuum; the residue is dissolved in a9:7-mixture of benzene and chloroform and the solution is filteredthrough neutral alumina (activity III), to yield mg. of A-3:17-dioxo-1OB-acetoxy-19-n0randrostadiene which decomposes at ISO-200C. after four recrystallizations from actone+petroleum ether. [a] +38(c.=1.37). Ultraviolet spectrum: A =250 m (e=l4,430). Infrared spectrumin chloroform: 11 1730-1740 (broad). 1665, 1628, 1611, 1249 cmr Example5 A solution of 98 mg. of A -3:17-dioxo-10B-acetoxy-19- norandrostene in10 cc. of tetrahydrofuran is added dropwise at 0 C. to a suspension of200 mg. of lithium tritertiary butoxy aluminum hydride in 5 cc. oftetrahydrd furan and the reaction mixture is stirred for 20 minutes at 0C. The excess reducing agent is decomposed with 10 cc. of aqueous aceticacid of 5% strength, the whole is extracted with ether, and the organicphase is washed with sodium bicarbonate solution and with water. Whenthe resulting crude product is recrystallized, once fromacetone+petroleum ether, it yields "/0 mg. of pure A -3-oxo-IOfi-acetoxy l7fl-hydroxy 19 norandrostene melting at 153-156 C. Opticalrotation [a] =+49 (c.=1.l0). Ultraviolet spectrum: A =244 m (e:15,150).Infrared spectrum in chloroform: u 3620, 1733, 1666, 1625, 1250 cmfExample 6 Example 7 A solution of 150 mg. of A-3-oXo-10fi:17B-diacetoxy- 19-norandrostene in 6 cc. of tertiary butanoland 0.8 cc. of glacial acetic acid is mixed with 100 mg. of seleniumdioxide and the whole is boiled for 6 hours while being stirred. Another100 mg. of selenium dioxide are then added and the mixture is heated for30 minutes longer. The cooled solution is decanted, the residue iswashed with ethyl acetate and evaporated under vacuum. The residue istaken up in ethyl acetate and the solution is successively washed withsodium bicarbonate, ammonium bisulfite, ammonia solution, sulfuric acidand water. Yield: 165 mg. of an oil which is chr-omatographed on neutralalumina (activity III). A 9:1-mixture of benzene and chloroform elutes46 mg. of A -3-oXo-10,6:17;3- diacetoxy-19-norandrostadiene which, afterone recrystallization from aqueous methanol, melts at 213 215 C. Opticalrotation [cc] =-32 (c.=0.87, in chloroform). [a] =30 (c.=-0.80, indioxane). Infrared spectrum in chloroform: v =1725 (broad), 1660, 1621,1600. 1240 cmr Example 8 A suspension of 36 grams of previously driedlead and yields the A -3:17-dioxo-10f3-acetoxy-19-norandrostadienemelting at 165 C., [a] =,+162 (c.=0.6 in chloroform); yield 70 to 80%.

Example 9 According to the method described in Example 8, 1.2 grams of A-3 20-dioxo-17ot-acetoXy-19-hydroxypregnadiene are heated together with4.0 grams of lead tetraacetate, 1.2 grams of calcium carbonate and 250cc. of benzene and worked up. There are obtained 1.5 grams of asemicrystalline crude product which yields after chromatography onneutral alumina (activity III) 810 milligrams of pure A-3:2O-dioXo-10fi:17a-diacetoxy-19-nor- 6 pregnadiene melting at C.contains absorption bands, inter alia, at 5.75, 5.79, 6.00,

6.17, 6.27 and 8.19;, ultra-violet spectrum: k =285 m What is claimedis:

1. Process for the manufacture of 10B-acyloXy-19-norsteroids, wherein aA -3oXo-19-hydroxysteroidis treated with a heavy-metal acylate having anoxidizing action;

2. Process according to claim 1, wherein an acylateof tetravalent leadis used as heavy metal acylate.

3. Process according to claim 2, wherein lead tetraacetate is used. e

4. Process according to claim 1, wherein the treatment with a heavymetal acylate is carried out in an apolar solvent.

5. Process according to claim 4, wherein a member selected from thegroup consisting of benzene and cyclohexane is used.

6. Process according to claim 1, wherein the treatment with a heavymetal acylate is carried out in the presence of a weak base.

7. Process according to claim 6, wherein calcium carbonate is used.

8. Process according to claim 1, wherein A -3-oXo-19-hydroXy-androstenes are used as starting material.

9. Process according to claim 1, wherein A -3-oXo-19- hydroxy-pregnenesare used as starting material.

10. Process according to claim 1, wherein A -3-oxo-19-hydroxy-androstadienes are used as starting material.

11. Process according to claim 1, wherein A -3-oxo-19-hydroXy-pregnadienes are used as starting material.

12. Process according to claim 1, wherein A -3zl7- dioxo-l9-hydroxyandrostene is used as starting material.

13. Process according to claim 1, wherein A -3:20dioxo-17u-acetoxy-19-hydroxy-pregnene is used as starting material.

14. Process according to claim 1, wherein A -3:17-di- IoXo-19-hydroXy-androstadieneis used as starting material.

15. Process according to claim 1, wherein 11 -3 :20- dioxo 17a acetoxy19 hydroxy-pregnadiene-is used as starting material.

16. A4:6-3-OXO-10,B acyloxy 19 norandrostadienes in References Cited bythe Examiner UNITED STATES PATENTS V 1/56 Colton 260397.4

2,882,282 4/59 Agnello et al. 260397.3 2,891,079 6/59 Dodson et al.260-3974 2,910,486 10/59 Jiu 260-397.4

OTHER REFERENCES Amorosa et al.: Helv. Chim. Acta, pp. 2674-2 698(1962).

LEWIS GOTTS, Primary Examiner.

Its infrared spectrum 0 IJ'NITED STATYES :PATENT ()FFICE CERTIFICATE OFCORRECTION Patent No. 3,178,461 April 15, 1965 Oskar Jeger et :11.

It is hereby certified that error appears in the above numbered petentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 6, line 45, for "-norandrostane" read norandrostadiene Signed andsealed this 18th day of January 1966.

( L) Attest:

ERNEST W. SWIDER 'EDIWARDJ. BRENNER Attesting Officer Commissioner ofPatents

1. PROCESS FOR THE MANUFACTURE OF 10B-ACYLOXY-19-NORSTEROIDS, WHEREIN A$4-3-OXO-19-HYDROXYSTEROID IS TREATED WITH A HEVY-METAL ACYLATE HAVINGAN OXIDIZING ACTION.
 17. $4:6-3:17-DIOXO-10B-ACETOXY-19-NORANDROSTANE.